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Metallomics [BCB, POMAM]

May 2 2019

Summary:

Thiosemicarbazones (TSCs) are a class of strong metal ion ligands, which are currently being investigated for several applications, such as anticancer treatment. In addition to these ligands only,

which exert their activity upon interaction with metal ions in cells, preformed metal–TSC complexes are also widely studied, predominantly with the essential metal ions iron, copper and zinc. A proposed advantage of using essential metal ions is the expected lower side effects. Currently, it is unclear what the active species are, which complexes are present and what are their biological targets.

In our contribution, we study the complexes of copper(II), zinc(II) and iron(II) with three TSCs, PT, 3-AP (triapine) and Dp44mT, (latter two are currently in clinical trials), concerning their reactivity with glutathione (GSH) and Zn7-metallothionein (Zn7MT-1, 2 and 3). These two cysteine-containing molecules can have a major impact on metal–TSC complexes because they are abundant in the cytosol and nucleus, they are strong metal ligands and have the potential to reduce Cu(II) and Fe(III). Our results indicate that Fe(II)–TSC is stable in the presence of typical cytosolic concentrations of GSH and Zn7MT. In contrast, all three Cu(II)–TSCs react rapidly due to the reduction of Cu(II) to Cu(I), which is then transferred to MT. This suggests that Cu(II)–TSCs are rapidly dissociated in a cytosolic-type environment and the catalytic generation of reactive oxygen species by Cu(II)–TSCs is stopped. Moreover, in the case Cu(II)–Dp44mT, transmetallation with Zn(II) from MT occurs. The reaction of Zn(II)–TSCs is ligand dependent, from predominant dissociation for PT and 3-AP, to very little dissociation of Zn(II)–Dp44mT2.

In summary our results show that MT can be a very important modulator of Cu(II)-TCS complexes, leading to either disruption or transmetallation. Moreover, it also shows that MT will prevent TSC to acquire Cu(I) in the cytosol. Thus, MT together with GSH, should be taken into account for the design of metal- and in particular Cu-complexes that are designed to interact as a complex with a target in the cytosol or nucleus for all the wide applications in biology and medicine, such as cancer treatment, imaging, antimicrobials.  

 

Reference:

Alice Santoro, Bertrand Vileno, Òscar Palacios, Manuel David, Peris-Díaz, Gilles Riegel, Christian Gaiddon, Artur Krężel and Peter Faller

Reactivity of Cu(II)–, Zn(II)– and Fe(II)–thiosemicarbazone complexes with glutathione and metallothionein: from stability to dissociation to transmetallation

Metallomics, Accepted 4th April 2019 - DOI :10.1039/c9mt00061e

 

Contact chercheur :

Alice Santoro (alice.santoro@unistra.fr), Peter Faller  (pfaller@unistra.fr), équipe BCB, and Bertrand Vileno (vileno@unistra.fr) équipe POMAM, Institut de Chimie (UMR7177).